Maladaptive cAMP-dependent protein kinase A (PKA)-mediated phosphorylation and redox-dependent modifications (thio-nitrosylation and oxidation) of the RyR2 contribute to impaired Ca2+ handling and contractile dysfunction in heart failure, diabetes and muscular dystrophies including the severe Duchenne muscular dystrophy (DMD). Single-point mutations of RyR2 are also linked to cardiomyopathies such as catecholaminergic polymorphic ventricular tachycardia (CPVT).

Using animal models, we have previously shown that SR Ca2+ leak mediated by RyR2 remodeling due to post-translational modifications (DMD) or single-point mutations (CPVT), can cause ventricular tachycardia, sudden cardiac death under stress conditions such as beta-adrenergic stimulation, and/or dilated cardiomyopathy leading to heart failure. However, the animal models classically used do not always recapitulate the phenotype seen in patients and it is ethically impossible to obtain fresh cardiac ventricular biopsies from patients.

Therefore, to further validate the role of RyR2 in DMD and CPVT patients, we hypothesize that human induced-pluripotent stem cells (hiPSC)-derived cardiomyocytes (CMs) from DMD and CPVT patient biopsies represent an excellent ex vivo alternative model to investigate Ca2+ handling abnormalities in CMs lacking dystrophin and in CMs harboring RyR2 single-point mutations (Fig. 1 and 2).

Overall, the main objective of this research project is to provide a deeper knowledge about the basic mechanisms initiating and responsible for cardiomyopathies related to DMD and CPVT. Another objective is also to screen new pharmacological tools to treat those cardiac disorders by targeting specifically RyR2.